A critical appraisal of the tafazzin knockdown mouse model of Barth syndrome: what have we learned about pathogenesis and potential treatments?

Abstract

Pediatric heart failure remains poorly understood, distinct in many aspects from adult heart failure. Limited data point to roles of altered mitochondrial functioning and, in particular, changes in mitochondrial lipids, especially cardiolipin. Barth syndrome is a mitochondrial disorder caused by tafazzin mutations that lead to abnormal cardiolipin profiles. Patients are afflicted by cardiomyopathy, skeletal myopathy, neutropenia, and growth delay. A mouse model of Barth syndrome was developed a decade ago, which relies on a doxycycline-inducible short hairpin RNA to knock down expression of tafazzin mRNA (TAZKD). Our objective was to review published data from the TAZKD mouse to determine its contributions to our pathogenetic understanding of, and potential treatment strategies for, Barth syndrome. In regard to the clinical syndrome, the reported physiological, biochemical, and ultrastructural abnormalities of the mouse model mirror those in Barth patients. Using this model, the peroxisome proliferator-activated receptor pan-agonist bezafibrate has been suggested as potential therapy because it ameliorated the cardiomyopathy in TAZKD mice, while increasing mitochondrial biogenesis. A clinical trial is now underway to test bezafibrate in Barth syndrome patients. Thus the TAZKD mouse model of Barth syndrome has led to important insights into disease pathogenesis and therapeutic targets, which can potentially translate to pediatric heart failure.

Barth Syndrome: Exploring Cardiac Metabolism with Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Other studies involved cellular models such as fibroblasts [35], lymphoblasts [36], neutrophils [37], neonatal ventricular fibroblasts [38], and cardiac myocytes [39]. Later, mouse models were generated and revealed multiple cardiac and muscle dysfunctions [40,41] and disruption of the interactions between the electron transport chain (ETC) and some fatty acid oxidation enzymes [42].…”

Cardiolipin deficiency in Barth syndrome is not associated with increased superoxide/H2O2 production in heart and skeletal muscle mitochondria

“…Nearly a decade ago, the first mouse model expressing an inducible short‐hairpin RNA to promote taz knockdown (tazkd) became available [6,10]. Tazkd mice recapitulate many aspects of the disease in humans; however, the symptoms in the murine model are characterized by a much later onset where cardiomyopathy becomes evident at 8 months [6,11].…”

“…Due to the fact that different groups have reported higher production rates of mitochondrial oxidants in heart and skeletal muscle in BTHS [7,12,27–35], together with the encouraging effects of some antioxidants, especially mitoTEMPO and linoleic acid [12,35] for improving cardiomyopathy pathogenesis, mitochondrial superoxide/H 2 O 2 production is considered a key target for therapeutic interventions [3,11,12]. However, the precise site(s) responsible for the abnormal production of mitochondrial oxidants in different tissues in BTHS are still unknown.…”

The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action

“…Nascent CL is synthesized de novo within the MIM and subsequently undergoes a remodeling process to render mature species with a highly unsaturated complement of acyl chains that is species-and tissue-specific (24) (Figure S1B). Alterations in CL distribution and biogenesis are associated with a number of diseases (25), including Barth syndrome (26,27), which is caused by defects in the transacylase tafazzin with concurrent aberrant remodeling of CL and buildup of the its lysolipid form, monolysocardiolipin (MLCL). Hence, being critical for mitochondrial structure and function, the anionic phospholipids of mitochondrial membranes are promising targets for therapeutic agents.…”